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Attenuation of p38-Mediated miR-1/133 Expression Facilitates Myoblast Proliferation during the Early Stage of Muscle Regeneration

Authors
Journal
PLoS ONE
1932-6203
Publisher
Public Library of Science
Publication Date
Volume
7
Issue
7
Identifiers
DOI: 10.1371/journal.pone.0041478
Keywords
  • Research Article
  • Biology
  • Developmental Biology
  • Organism Development
  • Regeneration
  • Molecular Development
  • Genetics
  • Gene Expression
  • Rna Interference
  • Human Genetics
  • X-Linked
  • Duchenne Muscular Dystrophy
  • Gene Function
  • Model Organisms
  • Animal Models
  • Mouse
  • Molecular Cell Biology
  • Nucleic Acids
  • Rna
  • Signal Transduction
  • Signaling Pathways
  • Cell Division
  • Cell Growth
Disciplines
  • Musicology

Abstract

Myoblast proliferation following myotrauma is regulated by multiple factors including growth factors, signal pathways, transcription factors, and miRNAs. However, the molecular mechanisms underlying the orchestration of these regulatory factors remain unclear. Here we show that p38 signaling is required for miR-1/133a clusters transcription and both p38 activity and miR-1/133 expression are attenuated during the early stage of muscle regeneration in various animal models. Additionally, we show that both miR-1 and miR-133 reduce Cyclin D1 expression and repress myoblast proliferation by inducing G1 phase arrest. Furthermore, we demonstrate that miR-133 inhibits mitotic progression by targeting Sp1, which mediates Cyclin D1 transcription, while miR-1 suppresses G1/S phase transition by targeting Cyclin D1. Finally, we reveal that proproliferative FGF2, which is elevated during muscle regeneration, attenuates p38 signaling and miR-1/133 expression. Taken together, our results suggest that downregulation of p38-mediated miR-1/133 expression by FGF2 and subsequent upregulation of Sp1/Cyclin D1 contribute to the increased myoblast proliferation during the early stage of muscle regeneration.

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